1. Field of the Invention
The present invention relates to a solid preparation having a purpose and function of regulating the rate of releasing a medicine administered mainly orally in the digestive tracts and a process for producing it. In particular, the present invention relates to a multi-layer solid preparation characterized by having an outer layer comprising a plasma-decomposable polymer and a plasma-crosslinkable polymer and irradiated with a plasma for the above-described purpose and for obtaining the above-described function, and a process for producing it.
2. Description of the Prior Art
The matrix method is a method of designing a preparation having a purpose and function of regulating the rate of releasing a medicine in the digestive tracts. It is known to use a water-insoluble substance such as a wax or ethylcellulose as the material of the matrix. The matrix method is characterized by a mesh structure comprising a skeleton of a water-insoluble substance such as a wax or ethylcellulose. The rate of releasing the medicine from the mesh structure upon contact with the fluid in the digestive tracts is regulated by varying the properties of this structure.
The release of a medicine from the mesh structure depends mainly on a difference in the osmotic pressure between the inside and outside of the structure or, in other words, difference in the concentration of the medicine between them. Since the difference in concentration does not change for a considerably long time in the mesh structure, there is a tendency toward a zero-order release rate. Therefore, when a zero-order release rate was desired, a matrix-type preparation was frequently used heretofore. As the rate constant of the zero-order release varies depending on the size of the openings of the mesh and their uniformity, it is important to select the most suitable technique and contrivance for forming the openings of the mesh. Various techniques were developed for this purpose. They include a technique wherein a medicine-containing solid preparation is irradiated with .gamma.-rays to form a mesh structure and a technique wherein the medicine-containing solid preparation is coated with a film comprising a water-soluble substance such as a sugar so that the water-soluble substance is eluted to form the mesh structure after the administration thereof. However, these methods still have problems. Namely, in the .gamma.-ray irradiation method, the medicine is decomposed and deactivated and in the latter method, the coating film containing the water-soluble substance will be affected by the conditions in the digestive tracts.
The inventors have made intensive investigations for the purpose of developing a new functional material by a plasma reaction and, more particularly, for the purpose of developing a new drug delivery system with a plasma-irradiated polymer powder. The following references 1), 2) and 3) written by the inventors are to be referred to in the present invention:
1) Bulletin of the Gifu College of Pharmacy, Vol. 36 (1987), pp. 11 to 25, Masayuki KUZUYA New Plasma-started Polymerization, PA1 2) "Chemical Engineering" published by Kagaku Kogyo-Sha in 1989, pp. 664 to 671; Masayuki KUZUYA, New DDS with Plasma-irradiated Polymer Powder, and PA1 3) "Hyomen" published by Koshin-Sha in 1989, pp. 885 to 892.
It is well known that when an acrylic resin such as polymethyl methacrylate is subjected to radical irradiation, radicals are formed on the resin surface. The inventors have found that when a plasma-irradiated acrylic resin is tableted as indicated in References 2) and 3), the radicals on the resin surface cause crosslinking between the solids due to the compression in the tableting operation to form macro-matrix tablets. Namely the inventors succeeded in forming a matrix having a mesh structure regulated at will by suitably selecting the irradiation polymerization conditions and tableting compression conditions, unlike known matrixes. The Reference 2) discloses a case wherein theophylline is incorporated into an acrylic resin powder irradiated with an argon plasma and tableted and the behavior of theophylline eluted therefrom is investigated. It is described therein that the mesh structure of the matrix can be regulated at will by suitably selecting the irradiation polymerization conditions and tableting compression conditions and that, as a result, the diffusion and elution of theophylline as the rate-determining step can be controlled.
Thereafter the inventors proposed various matrix-type release-regulating preparations according to the plasma irradiation and investigated them. The inventors thus found that by forming a multi-layer preparation comprising a tablet or granule containing a medicine as the core and the outermost layer comprising a plasma-decomposable polymer and a plasma-crosslinkable polymer and irradiating the outermost layer with a plasma, the direct exposure of the medicine to the plasma can be avoided and the release pattern can be controlled more easily. The present invention has been completed after further investigations made on the basis of this finding.
The present invention provides a multi-layer solid preparation characterized by having an outer layer comprising a plasma-decomposable polymer and a plasma-crosslinkable polymer and irradiated with a plasma. The present invention provides also a process for producing a multi-layer solid preparation characterized by forming an outermost layer comprising a plasma-decomposable polymer and a plasma-crosslinkable polymer and then irradiating the layer with a plasma.